Time Interval of Two Injections and First-Dose Dependent of Accelerated Blood Clearance Phenomenon Induced by PEGylated Liposomal Gambogenic Acid: The Contribution of PEG-Specific IgM |
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Authors: | Fengling Wang Xi Ye Yifan Wu Huihui Wang Chengming Sheng Daiyin Peng Weidong Chen |
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Institution: | 1. Institute of Drug Metabolism, School of Pharmaceutical Sciences, Anhui University of Chinese Medicine, Hefei 230012, Anhui, China;2. Department of Pharmacy, The Second People’s Hospital of Hefei, Hefei 230011, Anhui, China |
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Abstract: | Repeated injection of PEGylated liposomes can cause the disappearance of long circulating property because of the induction of anti-PEG IgM antibody referred to as “accelerated blood clearance (ABC) phenomenon.” Although ABC phenomenon typically occurs when entrapped drugs are chemotherapeutic agent with low cytotoxic, there is little evidence of accelerated blood clearance of PEGylated herbal-derived compound on repeated injection. Herein, we investigated the blood concentration of PEGylated liposomal gambogenic acid (PEG-GEA-L), a model PEGylated liposomal herbal extract, on its repeated injection to rats. We found time interval between injections had considerable impact on the magnitude of ABC phenomenon induced by PEG-GEA-L. When time interval was prolonged from 3 days to 7 days, ABC phenomenon could be attenuated. Furthermore, its magnitude was enhanced accompanied by a marked rise in the accumulation of PEG-GEA-L in the liver and spleen in a first-dose–dependent manner. Consistently, the level of anti-PEG IgM significantly increased with the first dose of PEG-GEA-L and decreased with the extended time interval between injections, which implies anti-PEG IgM is a major contributor to the ABC phenomenon. Notably, the increased expression of liver anti-PEG IgM was accompanied by an increased expression of efflux transporters in the induction process of the ABC phenomenon. |
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Keywords: | PEGylated liposome ABC phenomenon anti-PEG IgM gambogenic acid efflux transporters ABC accelerated blood clearance ABCA1 ATP-binding cassette transporters A1 ABCG1 ATP-binding cassette transporters G1 AUC area under the blood concentration time curve CL total body clearance DAPI 2-(4-Amidinophenyl)-6-indolecarbamidine dihydrochloride DLS dynamic light scattering EE encapsulation efficiency EPR enhanced permeability and retention GEA gambogenic acid HPLC high performance liquid chromatography MDR1 multidrug resistance protein 1 MPS mononuclear phagocyte system PDI polydispersity index PBS phosphatebuffered saline PEG polyethylene glycol PEG-empty-L empty PEGylated liposomes PEG-GEA-L PEGylated liposomal gambogenic acid PLD PEGylated liposomal doxorubicin SD standard deviation SEM scanning electron microscope TEM transmission electron microscopy |
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